Oseltamivir, and in particular its phosphate salt, is a potent inhibitor of neuraminidases (for an introduction see e.g. von Itzstein, M., Nature Reviews Drug Discovery (2007) 6, 12, 967-974) and is currently the best drug among the currently available anti-influenza treatments due to its good oral bioavailablity and tolerance. It acts to minimise the effects of flu by inhibiting the protein neuraminidase that lives on the flu virus cells. Oseltamivir was developed by Gilead Sciences, and it is currently marketed by Hoffman La Roche under the tradename Tamiflu. Influenza causes 20,000-40,000 deaths per year in the US alone. Additionally, the recent spread of the avian virus strain H5N1, found in birds and poultry (‘bird flu’, or ‘avian flu’), is causing great concern worldwide due to its severity with a lethality rate in humans of over 50%. According to the World Health Organization, about 200 deaths around the world since late 2003 had been officially attributed to H5N1 as of 2007. As the virus has become endemic in countries such as Indonesia and Vietnam there is fear that H5N1 will turn into a human form of influenza virus, giving rise to a pandemic.
Countries around the world have sought to stockpile Tamiflu against the possibility of global outbreak of a form of the avian virus that could be spread by humans. In 2008 Singapore announced it had already purchased 1.05 million courses of Tamiflu and intended to add a further 650,000 courses, while the British government was quoted to hold sufficient quantities of Tamiflu to treat one-quarter of its population. In the same year a British government report warned that the world was ill-prepared for an inevitable influenza pandemic. The report further warned that while the last two pandemics—in 1958 and 1968—were caused by relatively mild strains of influenza the next one could have more serious consequences, especially if it originated from H5N1. Accordingly, stockpiling led to an expansion of the manufacturer's production capacity to 400 m treatments annually already by the end of 2006 (Chemical News & Intelligence: Roche expands Tamiflu manufacturing network, Mar. 16, 2006) and caused some jurisdictions to issue a compulsory licence (World Markets Analysis: Authorities in Taiwan Issue Compulsory Licence for Tamiflu, Roche Responds with Supply Promise, Nov. 29, 2005).
Efficient and scalable synthesis is the key to meet the increasing global demand for this drug. The current commercial synthetic route involves a 10-step process of complex chemical reactions (e.g. Rohloff, J. C., et al., J. Org. Chem. (1998) 63, 4545-4550) and requires a production time of more than six months (The New York Times: Pressure Rises On Producer Of a Flu Drug, Oct. 11, 2005; The Washington Post: Run on Drug for Avian Flu Has Physicians Worried, Oct. 22, 2005; Yeung, Y. Y., et al., J. AM. Chem. Soc. (2006) 128, 6310-6311) and uses naturally occurring (−)-shikimic acid as a starting material. However (−)-shikimic acid is expensive and of limited availability, two-thirds of the current supply originate from one single source obtained from the pods of the Chinese star anise. The remaining third is obtained by fermentating E. coli bacteria (The International Herald Tribune: Roche bends to pressure on flu drug demand, Nov. 11, 2005). There is therefore a need for alternative synthesis routes.
Hence, new synthesis routes starting from other materials have been extensively investigated (see e.g. Farina, V., & Brown, J. D., Angew. Chem. Int. Ed. (2006) 45, 7330-7334), carried out largely by well-established research groups of Corey (Yeung, Y. Y., et al., 2006, supra), Shibasaki (Fukuta, Y., et al., J. AM. Chem. Soc. (2006) 128, 6312-6313; Yamatsugu, K., et al., Tetrahedron Lett. (2007) 48, 1403-1406; Mita, T., et al., Organic Lett. (2007) 9, 2, 259-262) and Cong (Cong, X., & Yao, Z. Y., J. Org. Chem. (2006) 71, 3565-5368). Starting materials used for forming Oseltamivir or derivatives thereof are 1,3-butadiene and acrylic acid (Yeung, Y. Y., et al., 2006, supra), fumaryl chloride and 1-(tert.-butyldimethylsiloxy-)-1,3-butadiene (Yamatsugu et al., 2007), L-serine (Cong, & Yao, 2006, supra), 3-amino-3-deoxy-1,2-O-isopropylidene-α-D-ribofuranose (Shie, J.-J., et al., J. AM. Chem. Soc. (2007) 129, 11892-11893), meso-aziridine (Fukuta et al., 2006, supra; Mita et al., 2007, supra), pyridine (Satoh, N., et al., Angew. Chem. Int. Ed. (2007) 46, 5734-5736) and [3aS-(3aα,6β,7α,7aα)]-3a,6,7,7a-tetrahydro-6,7-dihydroxy-5-(hydroxymethyl)-2-benzoxazolone (abstract of Korean patent application 2007-082985). After the priority date of the present application, Trost & Zhang (Angew. Chemie Int. Ed. Engl. (2008) 47, 3759-3761) furthermore presented the synthesis of Oseltamivir from racemic 6-Oxabicyclo[3.2.1]oct-3-en-7-one and a group at Hoffmann-La Roche Ltd disclosed a synthesis starting from 2,6-dimethoxyphenol that involves an enantioselective hydrolysis using pig liver esterase (Zutter, U., et al., J. Org. Chem. (2008) 73, 13, 4895-4902).
It is an object of the present invention to offer an alternative process of forming Oseltamivir or derivatives thereof.
This object is solved by a synthesis route as defined in the appended claims. The synthesis route can make use of easily available starting materials.